2. Academic Validation
  3. Macrophage-derived S100A9 promotes diabetic cardiomyopathy by disturbing mitochondrial quality control via STAT3 activation

Macrophage-derived S100A9 promotes diabetic cardiomyopathy by disturbing mitochondrial quality control via STAT3 activation

  • Int J Biol Sci. 2025 Apr 22;21(7):3061-3080. doi: 10.7150/ijbs.111128.
Shengqi Huo 1 2,  Moran Wang 1,  Min Du 1,  Bowen Ren 1,  Tianshu Yang 1,  Lulu Peng 1 3,  Yue Jiang 1,  Dewei Peng 1,  Lintong Men 1,  Wei Shi 1 2,  Junyi Guo 1 2,  Cuntai Zhang 4 2,  Jiagao Lv 1 2,  Sheng Li 1 2,  Li Lin 1 2
Affiliations

Affiliations

  • 1 Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, China, 430030.
  • 2 Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, China, 430030.
  • 3 Department of Cardiology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China, 430030.
  • 4 Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, China, 430030.
PMID: 40384874 DOI: 10.7150/ijbs.111128
Abstract

The macrophage-cardiomyocyte crosstalk as a potential intervention target for diabetic cardiomyopathy (DCM) remains deeper exploration. We found S100A9, as an immunoinflammatory mediator, was up-regulated in cardiomyocytes and macrophages in diabetic heart by single-cell analysis. Furthermore, F4/80+CCR2+S100A9+ macrophages in peripheral blood and heart both increased in diabetic mice. S100A9 blocking by paquinimod or macrophage depletion (clodronate) alleviated diabetes-induced cardiac dysfunction, inflammatory macrophage infiltration, serum pro-inflammatory cytokines. More importantly, diabetic cardiac dysfunction, myocardial remodeling, and inflammation could be suppressed by macrophage specific S100A9 knockout (S100a9flox/floxLyz2-Cre). S100A9 activation led to excessive mitochondrial fission, decreased Mitophagy flux, and elevated mitochondrial oxidative stress. In addition, proteomics and transcription factor profiling array unveiled S100A9 activated STAT3 in cardiomyocytes. Nevertheless, these effects were mitigated by STAT3(Y705F) mutation, STAT3 knockdown, or paquinimod. Our study highlights macrophage-derived S100A9 as a critical mediator for impaired mitochondrial quality control in diabetic cardiac dysfunction, and targeting S100A9 represents a promising therapeutic target.

Keywords

S100A9; STAT3; diabetic cardiomyopathy; macrophage; mitochondrial quality control.

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